Carboxylic acid amides and method for their preparation



United States 3,197,473 CARBOXYLIC ACID AMEBES AND METHQE FDR THEHRPREPARATIGN Josef Kiosa, Berlin-Zehlendorf, Germany, assignor to Messrs.H. Trcmmsdorfi, Aachen, Germany, a company of German N Drawing. FiledFeb. 25, 1963, Ser. No. 260,862.

Claims priority, application Germany, 1, E52,

4 Qlaims. cl. zed-2s? This invention relates to pyridine and quinolinecarboxylic acid amides and to a novel method for their preparation, bycondensation of pyridine and quinoline carboxylic acids with amines inthe presence of polyphosphoric acid.

The invention is concerned with the preparation of pyridine carboxylicacid amides having the formula R EN and qui-noline carboxylic acidamides having the formula wherein R is a member selected from the groupconsisting of hydrogen, alkyl of l to 2 carbon atoms, alkoxy of l to 2carbon atoms, and phenyl; R is a member selected from the groupconsisting of an alkyl radical, a benzene radical, and a heterocyclicradical; R is a memer selected from the group consisting of hydrogen andan alkyl radical, and a radical forming a closed hetero cyclic nitrogenring in conjunction with N and R These amides are prepared bycondensation of the corresponding pyridine and quinoline carb-oxylicacids with amines having the formula wherein R and R have thesignificance previously set forth. NR R can :form a closed ring such aspiperidine, morpholine, or pyrrolidine.

T he carboxylic acid amides of the invention are valuable intermediatesin the preparation of drugs and pharmaceuticals having propertiesresembling those of antipyiine.

As examples of the pyridine carboxylic acids which may be used asstarting materials there are listed:

Nicotinic acid (3-pyridine carboxylic acid) Picolinic acid (Z-pyridinecarboxylic acid) isonicotinic acid (4-pyridine carboxylic acid)6-methylpicolinic acid (dmethyl-Z-pyridine carboxyiic acid) As examplesof quinoline carboxylic acids which may be used as starting materialsthere are listed:

2-phenylquinoline-4-carboxylic acid2-phenyl-fi-methoxyquinoline-4-carboxy1ic acid In accordance with theinvention, there are employed as amines to be condensed with theaforementioned acids, primary aliphatic amines, particularly lower alkylamines, such as methylamine, ethylamine, and propylamine, and primaryarylamiues, including amino derivatives of henzene, such as aniline andsubstituted anilines, for example, 2,6-dimethylaniline, 0-, morp-chloraniline, o-toluidine, p-toluidine, and p-phenetidine.

ddd'lfild Patented duly 2?, 1965l-phenyl-2,3-dimethyl-4-arninopyrazolone- 5 ,ll-phenyl-Z-methyl-3-ethyl-4-amino-pyrazolon-( 5 l-phenyl-2,3-dimethyl-4-methyl amino-pyrazolon- 5) and 1- phenyl-Z,3-dimethyl-4-benzyl-amino-pyrazolone- It is already known to produce carboxylic acidamides directly from carboxylic acid and amines. The component areheated together for along time and the separated water continuouslydistilled. This process however has considerable disadvantages, such asdanger of decomposition, overheating, discoloration, and the like.

For thi reason it has already been proposed to use as dehydratin andcatalytically acting substances, the acid chlorides of phosphorus, suchas phosphorus trichloride, phosphorus oxychloride, or the chlorides ofsulphur. This process in fact has certain advantages relative to directheating of canboxylic acids with amines, the yields being morefavorable. In this case also there are encounered numerous technical andpreparative deficiencies. Thus, it is necessary to dilute the conversionmaterial with inert diluents. Suitable diluents for thi purpose arebenzene and. toluene. These diluents are inflammable; their use thusdemands special apparatus and safety measures. When using acid chlorideof phosphorus or sulphur considerable quantities of volatilehydrio'hal-ic acid occur during condensation, which have to be collectedand led away. Finally, tough compounds are produced during condensationwhich damage the stirring mechanisms and largely destroy them.

it has now been found that all these disadvantages may be overcome ifpyridine or quinoline carboxylic acids are condensed with amines in thepresence of polyphosphoric acid (tetraphosphoric acid).

The amines are mixed with carboxylic acids in molar ratio, employingfrom 3 to 5 times the quantity of polyphosphoric acid relative to thetotal conversion compound, and heating is effected to suitabletemperatures, expediently between 160180 C., but the suitable condensingtemperature has to be ascertained for each base. Highly fluid andthoroughly mobile compounds are obtained at -l00 C. It is not necessaryto stir these compounds. The heating lasts 1-3 hours. This compound isabsorbed in Water neutralized or rendered weakly alkaline with soda,ammonia or diluted alkali. The thus produced amides are obtained ingreat purity. The yield amounts to 70-95%.

The quantity of polyphosphoric acid used is in no way limited. It mayalso be used at l020 times the quantity relative to the added conversionquantity of carboxylic acid or amine. Instead of the preformedpolyphosphoric acid obtainable in commerce, it is also possible to usepolyphosphoric acid prepared in situ namely in such a manner that amixture of orthophosphoric acid with adequate phosphorus pentoxide istaken, so that by heating and stirring the mixture there is obtained aphosphorus pentoxide (4) The conversion requires only a fewmanipulations and is quickly completed.

The process operates very selectively. Only certain carboxylic acids,namely, pyridine and quinoline carboxylic acids, react with amines togive satisfactory yields of amides.

The process in accordance with the invention has a surprising andunexpected effect, since it is known that polyphosphoric acid willordinarily convert amides, by elimination of water, into nitriles andfinally also promotes manifold inner molecular condensations.

How advantageously the process in accordance with the invention operatescan be seen from the example for preparation of 4-(pyridine-carboxylicacid amides or alkyl amido)1-phenyl-2,3 dimethylpyrazolone-(S). Thesecompounds may be produced by converting pyridine-carboxylic acidchlorides with 4-amino-1-phenyl-2,3-dimethylpyrazolone-(S) (West Germanpatent specification No. 897,407). The production of pyridine-carboxylicacid halides is extremely inconvenient. Certain simplifications havealready been proposed (German patent specification No. 1,046,058). Thesimplifications concerned however are such which do not avoid the use ofpyridine-carboxylic acid chlorides. The process according to theinvention overcomes all these difiiculties in a simple and technicallysuperior manner, as will be explained below by way of some examples. a

' Example 1 100 g. 4-amino-1-phenyl 2,3 dimethyl-pyrazolone-(S are mixedwith 62 g. nicotinic acid. This mixture is charged in portions whilststirring in 300 g. polyphosphoric acid, which is heated to 100-110 C.The whole lot dissolves.

The thinly liquid melt is heated to 160-l80 C. It is left for 1 /2 to 2hours at this temperature, allows it to cool ofi to 100 C. and allowsthe melt to flow into approximately 0.5 to 1 litre of water. The clear,often yellowy brown colored solution is neutralized with soda.4-(pyridine-3-carboxylic acid amido) 2,3 dimethyl-lphenyl-pyrazolone-(Scrystallizes out, which is sucked 01f, washed with water and dried.M.P.: 254-25 6 C. Yield The crystals so obtained are suspended in about200-300 ml. water, and concentrated hydrochloric acid is added ,whilststirring until the crystals are completely dissolved.

The brown solution is stirred for 1-2 hours with 20-30 g. decolorizingcarbon or left to stand for 3-5 hours with occasional stirring and thenfiltered. The water-White filtrate is neutralized whilst stirring with a20% soda solution. The amide is precipitated in glittering, purely Whitecrystals. M.P.: 256-258 C. Yield 135-140 g.

Example 2 100 g. 4-arnino-1-phenyl-2,3-dimethyl-pyrazolone-(5) are mixedwith 300 to 400 g. polyphosphoric acid, thoroughly stirred and heated byoccasionally stirring to filtered, so that a water-white filtrate isobtained. This filtrate is neutralized with a diluted aqueous ammoniasolution. (In this case no extensive heating is to take place.) Then4-(pyridine-3-carboxylic acid amido)-2,3-dirnethyl-l-phenyl-pyrazolone-(S) is precipitated as snowwhiteglittering crystals which melt sharply at 25 6-25 8 C.

Further purification is not longer necessary. Yield: 145 g.

Likewise it is possible to produce from:

4-arnino-1-phenyl-2,S-dimethyl-pyrazolone-(5) and isonicotinicacid:4-(pyridine-4-carboxylic acid amido)- Likewise from:

Aniline and nicotinic acidzpyridine-3-carboxylic anilide,

M.P.: 118-120" C. Yield: 65%.

p-Phenitidine and nicotinic acidzpyridine-3-carboxylic acid-p-ethoxyanilide, M.P.: l70-l72. Yield: 70%.

Picolinic acid and p-toluidinezpicolinic acid-p-toluide,

M.P.: 103-105- C. Yield: 70%.

Picolinic acid and o-toluidinezpicolinic acid-o-toluide,

M.P.: 64-66 C. Yield: 70%.

Isonicotinic acid anddiethylamine:isonicotinic acid-diethylamide, M.P.:23-25 C. Yield: 73%.

What is claimed is: 1. In the method for the preparation of carboxylicacid amides selected from the group consisting of v (l) R1 R 'd-N and 0/R1 R LN wherein R is a member selected from the group consisting 'ofhydrogen, alkyl of 1 to 2 carbon atoms, alkoxy of l to 2 carbon atoms,and phenyl; R is a member selected from the group consisting of an alkylradical, a benzene radical, and a heterocyclic radical; R is a memberselected from the group consisting of hydrogen and an alkyl radical, anda radical forming a closed heterocyclic nitrogen ring in conjunctionwith N and R the improvement which comprises condensing'a carboxylicacid selected from the group consisting of and R fie 0 o H with an amineof the formula /Ri HN wherein R, R and R have the foregoingsignificance, in the presence of polyphosphoric acid.

2. Method according to claim 1 in which the condensation is carried outat a temperature between about and about C.

3. The method which comprises reacting nicotinic acid 3,197,473 5 6 with4 amino-1-pheny1-2,3-dimethy1pyrazo1one in the References Citefi by theExaminer presence of polyphosphoric acid at a temperature between N n ATI about 160 C. and about 180 C. to form the correspond U STATES P EN 8 ii 2,304,830 12/42 Katzmann 260-2955 4. The method which cornyrisesreacting isonicotinic 5 2,939,661 5/61 H3111 et a1 200-394 acid with4-amino-1-pheny1-2,3-dimethylpyrazolone in the FOREIGN PATENTS presenceof polyphosphoric acid at a temperature between 450 051 7/36 GreatBrifaip about 160 C. and about 180 C. to form the corresponding amide"NICHOLAS S. RIZZO, Primary Examiner.

1. IN THE METHOD FOR THE PREPARATION OF CARBOXYLIC ACID AMIDES SELECTEDFROM THE GROUP CONSISTING OF